Abstract/summary Traumatic brain injury (TBI) is a major cause of disability in both the short term and the long term. There are few evidence-based treatment options for long-term TBI disability, but some medications, such as methylphenidate, are commonly used in clinical settings. Methylphenidate improves symptoms of chronic TBI, including attention deficits, cognitive disability, and fatigue, in some patients. But it is not yet possible to predict which patients are most likely to benefit from methylphenidate or other pharmaceuticals used in chronic TBI. This is at least in part because the pathophysiology of TBI-related disability is not well understood. However, metabolic changes occurring early after TBI are known to underlie at least part of the dysfunction that occurs acutely. Our pilot data from nuclear magnetic resonance (NMR)-based metabolomics studies reveal evidence of lasting changes in brain metabolism in resting animals with chronic TBI. The presence of this dysregulation suggests that lasting changes in brain metabolism could contribute to chronic TBI pathology. Clinical evidence also supports an interaction between brain metabolism and efficacy of medications including methylphenidate. However, the nature of this interaction is not yet clear, and it is not known how the chronically injured brain responds metabolically to behavioral testing or to medications. This is an important question, because a better understanding of how medications or other interventions affect brain metabolism could lead to a better ability to predict and monitor response to treatment. We hypothesize that long-term metabolic derangement in TBI contributes to chronic functional deficits. We further predict that treatment with methylphenidate will alleviate some functional deficits, and restore brain metabolism toward a normal pattern. We propose two aims to test this hypothesis, and to develop better methods for investigating brain metabolism. Aim 1 will determine the effects of methylphenidate on the metabolic response to brain injury and behavioral testing in chronically injured animals. Aim 2 will establish a protocol for isotopic labeling of metabolic products in experimental animals in our chronic TBI model to allow more detailed analysis of metabolic changes in chronic TBI. These studies will also allow us to analyze the correlation between behavioral performance to defects in metabolic pathways. At the successful conclusion of these studies, we will have determined the effect of methylphenidate on brain metabolism in chronic TBI, and on the injured brain's metabolic response to behavioral testing. We will also have developed expertise in a method for more deeply probing metabolic changes in TBI or other disease states. The results of these investigations will provide a foundation of preliminary data for future studies designed to develop use of the metabolic state of the brain as a biomarker for TBI pathology, and for prediction and monitoring of treatment efficacy.